The goal of project 2 is to investigate the role of lipoprotein lipase (LPL) in lipoprotein metabolism, energy homeostasis and atherogenesis. The experimental approach will center on establishing a line of LPL knockout mice which will be cross-bred with transgenic mice expressing both LPL in a tissue specific manner and/or other genes involved in lipoprotein and energy metabolism. LPL is one of the key lipoprotein modifying enzymes, catalyzing the hydrolysis of triglyceride rich lipoproteins, and therefore this project is directly related to the theme of the program project grant - namely, the investigation of lipoprotein metabolism and atherogenesis using tissue culture and genetically manipulated mice. The specific aims of this project are: (1) to rescue the LPL deficient mouse and thereby establish a line to study LPL functions as well as the biochemical and physiological consequences of LPL deficiency, (2) to create transgenic mice that selectively express LPL in a tissue specific manner to study the role of LPL in the tissue distribution of calories and int he determination of body mass composition, and (3) to assess the role of LPL in atherosclerosis. These studies will involve extensive interaction with he transgenic core facility as well as projects 1 and 5. The results of these studies will provide new information regarding the role and importance of LPL in both lipoprotein metabolism and, more generally, in energy homeostasis. In particular, information gained from aim 2 will directly address hypotheses implicating LPL ina the development of obesity and cachexia. Aim 3 will develop and use methods to specifically assess macrophage LPL and thus, will determine the role of macrophage LPL in the pathogenesis of atherosclerosis.